The Neuron as a Cell: Can IP3 Mediated Dendritic Ca2+ Waves Contribute to Altered Integration and Persistent Activity in Cortical Neurons?

第二信使介导的细胞内Ca2+释放机制将纳入皮层锥体细胞的详细室室模型。研究人员和其他人已经在实验中观察到神经元树突中Ca2+释放的这些波，这些详细的细胞模型将用于复制这些波，研究它们的功能，并为未来的实验做出预测。这项工作的关键新颖方面是将细胞内信号通路的非线性动力学与神经元的电行为联系起来。这代表了一个根本性的转变，因为在过去的神经计算模型中，与细胞内信号传导相关的变化在很大程度上是作为静态参数变化实现的。详细的生物物理模型将使研究人员能够测试神经元内部生物化学是否可以改变皮质神经元的整合特性，以及这些细胞内过程是否可以影响神经元网络的行为。神经元细胞内Ca2+信号问题与理解可塑性机制和理解已知涉及细胞内信号通路故障的疾病过程具有直接相关性。可重复使用的工具将为NEURON通用模拟器精心制作，这将允许其他人用细胞内信号机制扩展广泛不同的神经模型，并探索各种相关问题。就更广泛的影响而言，该项目将汇集计算神经科学和计算细胞生物学领域-目前没有太多重叠的社区-以便开始研究理论神经科学目前尚未解决的神经元功能的许多方面。作为这项工作的一部分，伊利诺伊大学芝加哥分校将为本科生多样性项目提供研究经验机会。

Second messenger-mediated intracellular Ca2+ release mechanisms will be incorporated into detailed compartment models of cortical pyramidal cells. The investigators, as well as others, have observed these waves of Ca2+ release in neuronal dendrites experimentally, and these detailed cellular models will be used to replicate the waves, investigate their function, and make predictions for future experiments. The key novel aspect of this work is linking the nonlinear dynamics of the intracellular signaling pathways to the electrical behavior of the neuron. This represents a fundamental shift because changes related to intracellular signaling have largely been implemented as static parameter changes in past neurocomputational models. Detailed biophysical models will enable the investigators to test whether the internal neuronal biochemistry can function to alter integration properties of cortical neurons and whether these intracellular processes can affect the behavior of networks of neurons.The problem of intracellular Ca2+ signaling in neurons has immediate relevance for understanding mechanisms of plasticity and for understanding disease processes that are known to involve malfunctions of intracellular signaling pathways. Reusable tools will be crafted for the NEURON general-purpose simulator that will allow others to extend widely different neural models with intracellular signaling mechanisms and explore a variety of related problems. In terms of broader impact, the project will bring together the fields of computational neuroscience and computational cell biology - communities that do not currently overlap a great deal - in order to start to investigate the many aspects the function of neurons not currently addressed by theoretical neuroscience. As part of this work, research experience opportunities for undergraduate diversity programs will be provided at the University of Illinois at Chicago.